According to the annual report of the American Liver Foundation in 2000, hepatitis and other liver diseases affect 25 million Americans. Liver failure is the 8th most frequent cause of death in the United States, accounting for roughly 43,000 deaths each year. Liver transplantation is currently the only effective treatment for medically refractory liver failure. Liver transplantation has some shortfalls, however, including a shortage of donor organs, restrictions on potential recipients, and side effects of drugs used to prevent rejection after transplantation. The problem of organ scarcity is demonstrated by the fact that nearly 2000 candidates for liver transplantation died on the waiting list in 2003. Over 500 of these patients were listed with a diagnosis of fulminant hepatic failure (FHF). One potential solution to the shortage of organs is an extracorporeal liver support system, or bioartificial liver (BAL), which could serve as a bridge to transplantation or, in some cases, until spontaneous recovery of the native liver.
One goal of BAL therapy is to provide detoxification activity and preventing the systemic manifestations of acute liver injury as illustrated in FIG. 1. Current knowledge is that extrahepatic manifestations of ALF, such as brain edema, lung dysfunction, and renal dysfunction, result from a two-hit process: 1) systemic inflammatory response syndrome (SIRS); 2) occurring in the setting of inadequate hepatic synthetic and detoxification activities. The inflammatory response of ALF is mediated by cytokines, such as TNFα, that can be released from the acutely injured liver, while toxins such as ammonia apply a direct cytotoxic influence on target organs and their supporting cells. In support of this theory is the observation that SIRS is seen in at least 60% of ALF cases.
Ammonia, normally eliminated by the liver, is the most important toxin of the two-hit hypothesis outlined in FIG. 1. Arterial concentrations of ammonia have been shown to correlate with cerebral herniation in pediatric patients with urea cycle disorders and in many, but not all, ALF patients. TNFα is also an important marker of SIRS and the two-hit hypothesis of ALF. Furthermore, cytokines such as TNFα are believed to mediate the local inflammatory response and brain edema of head trauma. Therefore, it is highly conceivable that a synergism exists between inflammation and ammonia resulting in extrahepatic manifestations of ALF, such as brain edema.